Drug abusers have high rates of respiratory tract infections and are accelerated progression of AIDS, suggesting host immune defense is down-regulated in this group of patients. We have been investigating the mechanisms underlying the observation that pneumonias accelerate the course of AIDS and have observed that HIV-1 replication and mutation are increased by pulmonary tuberculosis (TB). We have embarked on an investigation of other arms of the immune system impact on HIV-1 replication. This has led to the observation that adenosine deaminase that acts on RNA-1 (ADAR1) may play an important role in the control of HIV-1 replication in the lung. In some ways ADAR1 is similar to the RNA editing enzyme cytidine deaminase that has recently been shown the innate immunity to control HIV-1 replication. We present data the HIV-1 envelope is highly mutated when AIDS patients with TB are treated with interferon (IFN)-gamma. Sequence data demonstrate an extraordinary rate of A to G mutation. Since ADAR1 is an enzyme known to produce these mutations, we investigated the stimuli that effected ADAR1 expression. We show in vivo IFN-gamma treatment induced ADAR1 mRNA and in vitro IFN induces ADAR1 in macrophages. ADAR1 expression is reduced in pneumonia. Then, we developed an in vitro model system to investigate the impact of ADAR1 expression on HIV-1 replication and mutation. Our aim in this proposal is to understand how ADAR1 gene involves in early and late steps of the viral life cycles. We will use replication incompetent pseudotyped HIV-1 to study the impact of ADAR1 expression on early post entry events. We will induce ADAR1 expression with an expression vector or reduce ADAR1 expression with siRNA to investigate the impact of ADAR1 on HIV-1 replication and mutation. To investigate the impact of ADAR1 expression of post integration steps of the viral life cycle, we will use cell lines with integrated HIV-1 and assay the impact of ADAR1 expression on vial load and mutation rate. These studies will establish if ADAR1 impacts on viral replication and mutation and will be the basis of further investigation on the impact of drug abuse on the expression of ADAR1. [unreadable] [unreadable] [unreadable]